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SNPs Mutations Haplotypes. Sequence variations. http://www.ebi.ac.uk/mutations/. How much variation in human genome?. 3000 Mb; a SNP every 1kb = 3 milj. Underestimate? Rare ones might be the most interesting 40 000 genes x 100 variants = 4 milj. slow build-up

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snps mutations haplotypes
SNPs

Mutations

Haplotypes

Sequence variations

http://www.ebi.ac.uk/mutations/

how much variation in human genome
How much variation in human genome?
  • 3000 Mb; a SNP every 1kb = 3 milj.
    • Underestimate?
    • Rare ones might be the most interesting
  • 40 000 genes x 100 variants = 4 milj.
    • slow build-up
  • Bottlenecks in human population history!
variations
Variations
  • SNPs (Single Nucleotide Polymorphisms)
  • Indels, dinucleotide mutations
  • Mutations, polymorphisms
  • Chromosomal rearrangements
    • inversions
    • translocations
    • indels
levels of biological data
MutationsLevels of biological data

DNA

RNA

Polypeptide

Protein structure

Protein function

Protein interection pathways

Cellular dynamics

Tissue interactions

Organism (phenotype)

Population dynamics

uses of sequence variations
Gene

structure &

function

Diagnosis of

inherited

disorders

Evolution &

ecology

Trans-

plantation

Genetic

mapping

Tissue

typing

Forensics

Epidemi-

ology

Insurance

evaluation

?

Association

studies

Carrier

screening

Pharmaco-

genetics

Scientists

Biomed

students

Healthcare

professionals

"General

public"

Uses of sequence variations
data sources
Nucleotide sequences

Amino acid sequences

EMBL/GenBank/DDBJ

Non-redundant human sequence

SWISS-PROT

SNPs

Data sources

Central variation databases

Sequence alignments

Population studies

Direct submissions

Literature / Publishers

Single Locus Databases

Blood Cells, Molecules

and Diseases

HGVS

dna mutation checker v 2
DNA Mutation Checker v.2

Bio::LiveSeq

Bio::Variation

http://bio.perl.org/

slide8
SNPs
  • dbSNP
      • main repository
  • HGVbase
      • clean subset
  • TSC
      • verified SNPs
      • allele frequency project
  • National SNP projects
      • Japan, China, ...
slide9
SNPs
  • dbSNP #29
      • 2,673,925 (414,853 masked)
  • HGVbase #13
      • 1,451,426
  • TSC #10
      • 1,389,655
      • 1,062,212 mapped
hgvbase
HGVbase
  • Human Genome Variation database http://hgvbase.cgb.ki.se/
  • ex. HGBASE
  • Three part collaboration betweenTony Brookes (KI), Heikki Lehvaslaiho (EBI) and Peer Bork (EMBL).
    • text and homology searches
    • Distributions: SQL dump, XML, flat file, FASTA
snp synchronization
SNP synchronization

Ensembl

dbSNP

HGVbase

hgbase update
HGBASE update
  • Assays
  • Flanking sequence retrieval
  • Effects on predicted genes
  • Chromosomal locations
  • Similarity scoring
  • Haplotypes
  • WOW extensions

http://hgbase.cgb.ki.se/

mutation numbering options
Mutation numbering options

Reference

Sequence

Numbering

Schema

-1 +1

Coding region

cDNA

DB entry

Coding region

gDNA

DB entry

Genomic gene seq

slide15
HGVS
  • Human Genome Variation Society
      • http://www.hgvs.org/
      • ex. HUGO MDI
      • Society Journal: Human Mutation
  • “The Society aims to foster discovery and characterization
  • of genomic variations including population distribution and
  • phenotypic associations.
  • We will promote collection, documentation and free distribution of
  • genomic variation information and associated clinical variations and
  • endeavor to foster the development of the necessary
  • methodology and informatics.”
a human sequence variation database emphasizing data quality and a broad spectrum of data sources
A human sequence variation database emphasizing data quality and a broad spectrum of data sourcesWaystationOfficeWarehouse

WOW

Jamie Cutticia

Dick Cotton

Heikki Lehväslaiho

Tony Brookes

wo warehouse plans
WOWarehouse plans
  • Expansion of the HGBASE design
  • Use of the Ensembl framework
  • Data flow from WayStation
      • Novel mutations
  • Direct parsing
      • Existing resources (SRS)
      • Need to get the the data in quickly
  • Haplotype & Genotype descriptions
  • Phenotype desciption
wow structure
Other

sources

LSDB

LSDB

LSDB

LSDB

ID

WayStation

Submitter

Warehouse

Updates

Downloads

PubMed

Human Mutation

Interfaces

LSDB

LSDB

LSDB

Editor

WOW structure

Correction requests

Downloads

Updates

Submission

Peer review

reference sequence
Reference Sequence
  • Strive to use genomic coordinates
  • Use Ensembl to visualise all variants in genomic context
  • Ensembl is now using NCBI genome builds => only one, up-to-date reference sequence
  • Easy way to transform gene coordinates into genomic coordinates
haplotype representation
Haplotype representation
  • Haplotype = list of Marker/AlleleIDs & HaplotypeIDs.
  • No ordering of IDs in Haplotype definition – taken care of by Marker definition.
  • No reference haplotypes
  • Genotype: >2 Haplotypes
haplotypes
Haplotypes
  • Chr21, 6 chromoses
    • David Cox (Patil et al, Science)
    • whole human genome coming
  • Chr22, >200 individuals
    • Ian Dunham, in preparation
  • Haplotype Blocks!
  • HapMap (Eric Lander, NIH)
phenotype
Phenotype
  • Pragmatic approach!
  • Ideas:
    • Based on extended GO terminogy developed at Jackson Laboratory
      • Phenotype = modifier + traits
    • OMIM compatible
    • US NML anatomy vocabulary subset?
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